Malaria:

Unmet Medical Needs and

The Urgent Need for a Vaccine

Miguel Prudêncio
5 July 2016
MALARIA: EPIDEMIOLOGY

Estimated P. falciparum infection prevalence among children aged 2–10 years (API,
annual parasite index; PfPR, P. falciparum parasite rate).
Source: WHO Malaria Report 2015
 MALARIA: PATHOGENESIS
Malaria: Pathogenesis

Respiratory distress, pneumonia, severe

anaemia, acute respiratory distress
syndrome, renal failure, cerebral malaria,
splenomegaly, and hemoglobinuria

Circulation
- Anemia
MALARIA: ETIOLOGY AND TRANSMISSION

The parasite The vector

Apicomplexa protozoa Female Anopheles mosquitoes

Plasmodium falciparum Anopheles gambiae

Plasmodium vivax Anopheles stephensi
Plasmodium ovale Anopheles dirus
Plasmodium malariae Anopheles atroparvus
Plasmodium knowlesi … and another 37 species

Plasmodium parasite Anopheles mosquito

PLASMODIUM LIFE CYCLElife cycle
Plasmodium
 ANTI-MALARIALPlasmodium
INTERVENTIONS
life cycle

INSECTISIDE-TREATED INSECTICIDES GM MOSQUITOES

MOSQUITO NETS

DRUGS VACCINES
MALARIA THERAPEUTICS: LIVER-STAGE

Primaquine

Primaquine is the only licensed antimalarial

compound acting on Plasmodium liver-stages.

Primaquine is mainly used for radical cure

(i.e., elimination of hypnozoites) of P. vivax or
P. ovale malaria.

Primaquine is highly toxic for individuals with

glucose-6-phosphate dehydrogenase (G6PD)
deficiency, a common trait in malaria-endemic
regions.
MALARIA THERAPEUTICS: BLOOD-STAGE

17th century 1930’s 1960’s 1972 2006 2008

Quinine Chloroquine Artemisinin Artemisinin-based

Combination
Therapies

Chloroquine was the main drug of choice
in the WHO Global Malaria Eradication
Programmes of the 1950s and 1960s.
Chloroquine resistance has now
spread to many of the areas of the
world where the infection is endemic.
Artemisinin became the treatment of choice for
malaria
The WHO called for an immediate halt to single-drug
artemisinin preparations, in favor of ACTs.
Signs of emerging artemisinin resistance were first
reported in Southeast Asia.
UNMET MEDICAL NEEDS IN MALARIA
THE URGENT NEED FOR A VACCINE
PRE-ERYTHROCYTIC MALARIA VACCINES
• Pre-erythrocytic stage vaccines have shown the
highest success among malaria vaccine candidates

•Subunit vaccines (RTS,S)

•Whole-organism vaccines
WHOLE-ORGANISM PRE-ERYTHROCYTIC
MALARIA VACCINES

• Whole-organism pre-erythrocytic vaccines are

based on the use of Plasmodium sporozoites, the
mosquito-resident, liver-infective forms of the
malaria parasite

• Whole-organism pre-erythrocytic vaccination is the sole

strategy shown to convey sterile immunity against malaria
 CURRENT W.O.P.E. VACCINATION
APPROACHES
Safety concerns
Rely on the use of P. falciparum sporozoites
No protection against P. vivax

Early liver stage arrest Administration of live,

Genetic revertants will
requires high numbers of non-attenuated
lead to disease
immunizing parasites P. falciparum sporozoites
 Thinking outside the species:
a rodent Plasmodium-based strategy
for vaccination against human malaria.
Plasmodium berghei

African thicket rat

A P. berghei-based vaccination platform
 P. berghei infectivity of human cells

Liver-humanized mice Blood-humanized mice

 Pb(PfCS@UIS4): Insertion of
P. falciparum circumsporozoite protein
 P. falciparum recognition and functional inhibition

Serum
collection

IFAT Passive transfer + Pf infection

of liver-humanized mice
1:1600 immune serum
dilution

P. falciparum
sporozoites
 Pre-Clinical Immunization Studies

PfCS-targeted

Cellular Cellular Humoral

immune responses immune responses &
Cellular
immune responses
Towards Phase 1/2a
clinical trials
Development of P. berghei-based vaccination platform

Multi-stage antigens

Multi-species antigens
 Acknowledgements

Robert W. Sauerwein Shahid Khan Iñigo Angulo-Barturem

Isaie Reuling Chris J. Janse Belen Jimenez-Diaz
António Mendes Rob Hermsen Ahmed Salman Sara Viera-Mollina
Maria M. Mota Merije Behet
Marta Machado Geert-Jan van Gemert
Jorge Santos Daphne Smit
Raquel Azevedo Anita van der Sanden
Inês Albuquerque Miguel Rodrigues
Joana Pissarra Thomas Dan Otto Pedro Rego
Carolina Andrade Mathew Berriman Rui Estrela
Dolores Bonaparte Chris Newbold
Nataniel Gonçalves-Rosa

Geert Leroux-Roels
Lander Foquet
Philip Meuleman Yimin Wu
Chris Ockenhouse
Cynthia Lee
Clemens Kocken Rick King
Ed Remarque
Anne-Marie Zeeman John Bial